Abstract Methicillin-resistant Staphylococcus aureus (MRSA) is one of the leading causes of many life-threatening infections such as skin and soft tissue sepsis, pneumonia, osteomyelitis and endocarditis. Due to the growing incidence of multiple drug resistance in S. aureus strains and the absence of effective new antibiotics, treatment options are becoming increasingly limited. Difficulties in developing new antimicrobials adds to the urgent need for developing a highly protective MRSA vaccine. Subunit protein- and polysaccharide-based vaccines have failed to trigger strong immune responses in clinical studies. We propose to assess a whole-cell vaccine approach which will contain multiple antigens/virulence factors to stimulate a more robust and protective immune response. We recently developed a novel method to produce gamma radiation- inactivated vaccines in the presence of a Mn antioxidant - MDP - derived from the extremely radiation-resistant bacterium Deinococcus radiodurans. Under aqueous conditions, MDP protects the surface proteins (epitopes) of cells and viruses from oxidative damage at supralethal radiation doses, yielding completely inactivated but highly immunogenic vaccine candidates. Applying this approach, we previously demonstrated that immunization with a gamma radiation-inactivated MRSA (Ir-MRSA using USA300 strain) vaccine candidate conferred protection from MRSA infection of skin wounds using a mouse model. We propose to extend these studies to evaluate the immunogenic and protective efficacy of a new Ir-MRSA vaccine candidate in a mouse model mimicking hospital-acquired (HA-MRSA) infections that are common surgical complications. To ensure a diverse expression of bacterial proteins, we propose to propagate the bacteria under different growth conditions designed to produce planktonic and biofilm forms. In addition, we will determine whether a vaccine made from HA- MRSA can stimulate cross-protection against challenge with a community-acquired (CA)-MRSA strain. Successful completion of these proposed studies and those to follow will result in a potential universal MRSA vaccine candidate suitable for human clinical trials.